Distinct Glycan Topology for Avian and Human Sialopentasaccharide Receptor Analogues upon Binding Different Hemagglutinins: A Molecular Dynamics Perspective

JOURNAL OF MOLECULAR BIOLOGY

卷:387

Review

Xu, Dong¹  Newhouse, E. Irene²  Amaro, Rommie E.^3,4  Pao, Hsing C.¹  Cheng, Lily S.¹  Markwick, Phineus R. L.⁵  McCammon, J. Andrew^1,3,4,5,6  Li, Wilfred W.¹  Arzberger, Peter W.¹ 

[1] Univ Calif San Diego, Natl Biomed Computat Resource, La Jolla, CA 92093 USA

[2] Maui High Performance Comp Ctr, Maui, HI USA

[3] Univ Calif San Diego, Dept Chem & Biochem, La Jolla, CA 92093 USA

[4] Univ Calif San Diego, Natl Sci Fdn, Ctr Theoret Biol Phys, La Jolla, CA 92093 USA

[5] Univ Calif San Diego, Howard Hughes Med Inst, La Jolla, CA 92093 USA

[6] Univ Calif San Diego, Dept Pharmacol, La Jolla, CA 92093 USA

关键词: avian influenza;    hemagglutinin;    glycan topology;    binding specificity;    molecular dynamics;   

DOI  :  10.1016/j.jmb.2009.01.040

来源: Elsevier

【 摘 要 】

Hemagglutinin (HA) binds to sialylated glycans exposed on the host cell surface in the initial stage of avian influenza virus infection. It has been previously hypothesized that glycan topology plays a critical role in the human adaptation of avian flu viruses, such as the potentially pandemic H5N1. Comparative molecular dynamics studies are complementary to experimental techniques, including glycan microarray, to understand the mechanism of species-specificity switch better. The examined systems comprise explicitly solvated trimeric forms of avian H3, H5, and swine H9 ill complex with avian and human glycan receptor analogues-LSTa (alpha-2,3-linked lactoseries tetrasaccharide a) and LSTc (alpha-2,6-linked lactoseries tetrasaccharide c), respectively. The glycans adopted distinct topological profiles with inducible torsional angles when bound to different HAs. The corresponding receptor binding domain ami-no acid contact profiles were also distinct. Avian H5 was able to accommodate LSTc in a tightly folded umbrella-like topology through interactions with all five sugar residues. After considering conformational entropy, the relative binding free-energy changes, calculated using the molecular mechanics-generalized Born surface area technique, were in agreement with previous experimental findings and provided insights on electrostatic, van der Waals, desolvation, and entropic contributions to HA-glycan interactions. The topology profile and the relative abundance of free glycan receptors may influence receptor binding kinetics. Glycan composition and topological changes upon binding different HAs may be important determinants in species-specificity switch. (C) 2009 Elsevier Ltd. All rights reserved.

【 授权许可】

Free